JP6280628B2 - Pain control pharmaceutical composition - Google Patents

Description

  The present invention relates to a pharmaceutical composition for suppressing pain in joint diseases, comprising crosslinked hyaluronic acid and a pharmaceutically acceptable carrier.

In today's aging society, osteoarthritis (hereinafter also referred to as OA), which is a dysfunction caused by joint pain and joint degeneration, is the most common joint disease in the world, It is one of the main causes of physical disability that interferes with daily life.
Currently, OA treatment includes oral administration treatment with analgesics such as non-steroidal anti-inflammatory agents widely used for various pains, and intra-articular treatment with hyaluronic acid solution.
The former is a symptomatic treatment method aimed at relieving joint pain with a synthetic pharmaceutical agent having a sharp analgesic effect.
On the other hand, the latter aims to treat joint diseases by reducing joint fluid and deteriorating joint function due to degeneration of joint cartilage, and by using hyaluronic acid's lubricating action, shock absorption action, cartilage metabolism improvement action and joint pain suppression action. The treatment method.
Hereinafter, in this specification, hyaluronic acid or a group derived therefrom may be abbreviated as “HA”.

  Currently, as intraarticular administration preparations using hyaluronic acid and its derivatives (hereinafter also referred to as IA-HA preparations), preparations comprising a sodium hyaluronate aqueous solution and preparations comprising a crosslinked hyaluronic acid derivative aqueous solution are commercially available. Yes. For example, as an IA-HA preparation comprising an aqueous sodium hyaluronate solution, Alz (ARTZ (registered trademark)), Synbisc (SYNVISC (registered trademark)), Hyalgan (HYALGAN (registered trademark)), Orthobisque (ORTHOVISC (registered trademark)) Etc. Examples of the IA-HA preparation comprising an aqueous crosslinked hyaluronic acid derivative solution include SYNVISC (SYNVISC (registered trademark)) and DUROLANE (registered trademark). Synvisc (SYNVISC (registered trademark)) is composed of a hyaluronic acid derivative covalently crosslinked with a small amount of aldehyde and a hyaluronic acid derivative obtained by further crosslinking the derivative with divinyl sulfone. Durolane (registered trademark) ) Is an epoxy-crosslinked joint protective agent (see Patent Document 1).

  These IA-HA preparations are basically administered every 1 to 2 weeks in order to obtain a desired therapeutic effect (see Non-Patent Documents 1 and 3). Since hyaluronic acid has viscoelasticity, intra-articular administration of these IA-HA preparations is performed using a needle that is thicker than normal injections. Therefore, invasion (sex) and puncture pain are more conscious than the usual injection administration, and the number of administrations in one treatment period is limited to 5 in principle in Japan. Moreover, since it is necessary to administer the conventional product continuously every week, it can be a heavy burden for patients who are remote from the hospital or who cannot visit every week due to work reasons. Therefore, a preparation that shows a therapeutic effect equivalent to or higher than that of a conventional IA-HA preparation with a small number of administrations has been desired.

Recently, as a new formulation using SYNVISC (SYNVISC (registered trademark)), a formulation (SYNVISC-ONE (trademark)) that is applied by single administration with a single dose (2 mL) increased three-fold has been reported. According to this, it is said that the therapeutic effect of 26 weeks after a single administration is shown (see Non-Patent Document 4). However, the therapeutic effect is only the result of administering the conventional three doses (6 mL) at a time, and the formulation of three times the conventional dose is injected into the joint at one time. There is also a demerit that the burden on the patient increases.
In addition, there is a report that a joint disease therapeutic agent for intra-articular administration using a photo-crosslinked hyaluronic acid derivative, which is a different crosslinking form from commercially available crosslinked hyaluronic acid, has a sustained effect by a single administration, No specific disclosure or suggestion has been made about the ultra-long-term persistence in human OA treatment (see Patent Document 2).

In addition, IA-HA preparations mainly aim to improve QOL of patients over a long period of time by improving overall joint function, and almost no immediate analgesic effect like non-steroidal anti-inflammatory analgesics is expected. (See Non-Patent Documents 1, 2, 4, and 5).
Although there are many IA-HA preparations as described above, an effect equivalent to or better than the effect of multiple administrations of the conventional IA-HA preparation can be achieved with one administration without increasing the dose of one administration. From the viewpoint of invasiveness over a long period of time, an intra-articular preparation that has been effective for more than half a year has not been reported.
Therefore, there has been a demand for a preparation that can exhibit a remarkable analgesic effect at an early stage, has as few administrations as possible, and has a therapeutic effect equivalent to or higher than that of conventional IA-HA preparations.

US Publication No. US2006 / 0148755 International Publication No. WO2008 / 069348

The Journal of Rheumatology 2004; 31: 4, pp.775-782 OsteoArthritis and Cartilage (2004) 12, 642-649 Current Medical Research and Opinion 11: 205-213, 1988 ARD Online First, published on March 19, 2009 as 10.1136 / ard.2008.094623 Arthritis & Rheumatism, Vol.43, No.9, pp.1905-1915 (2000)

  The present invention has a rapid analgesic effect after administration, and only administers a single dose, not a multiple dose, of a single dose of an IA-HA preparation used for conventional multiple doses. Thus, an object of the present invention is to provide a preparation for intra-articular administration that maintains an extremely long-term effect on human joint diseases.

  As a result of intensive studies in order to solve the above-mentioned problems, the inventors of the present invention have been said to have no early pain-reducing effect in conventional IA-HA preparations. It was found that pain was reduced early by using the crosslinked hyaluronic acid. In addition, when the preparation is administered once in an amount that is almost the same as the single dose of an IA-HA preparation that has been used for conventional multiple administrations, human joint diseases can be maintained for a long period of more than half a year. As a result, the present inventors have found that the effect can be sustained.

That is, the present invention provides the following general formula (1);
_{[Ar-CH = CH-COO-} (CH 2) n-NH-] m-HA (1)
(In the formula, Ar represents a phenyl group which may have a substituent, n represents 2 or 3, HA represents a carboxy residue of hyaluronic acid, and m represents amidation with respect to all carboxyl groups of hyaluronic acid. And m is 3 to 50% of the total carboxyl groups.)
A joint disease comprising hyaluronic acid crosslinked by cyclizing the double bond of the cinnamic acid moiety of the partially amidated hyaluronic acid represented by formula (II) and a pharmaceutically acceptable carrier The present invention relates to a pharmaceutical composition for suppressing pain in
The content of the crosslinked hyaluronic acid in the pharmaceutical composition is preferably 0.5% (w / v%) to 3.0% (w / v%) of the whole preparation.
The pharmaceutical composition is preferably a single dose preparation. In that case, it is preferable to administer at an administration interval of 13 weeks or more.
The pharmaceutical composition is preferably used for at least 13 weeks of sustained effect, more preferably for at least 26 weeks of sustained effect.

The present invention will be described in detail as follows.
(1) The following general formula (1);
_{[Ar-CH = CH-COO-} (CH 2) n-NH-] m-HA (1)
(In the formula, Ar represents a phenyl group which may have a substituent, n represents 2 or 3, HA represents a carboxy residue of hyaluronic acid, and m represents amidation with respect to all carboxyl groups of hyaluronic acid. And m is 3 to 50% of the total carboxyl groups.)
A joint disease comprising hyaluronic acid crosslinked by cyclizing the double bond of the cinnamic acid moiety of the partially amidated hyaluronic acid represented by formula (II) and a pharmaceutically acceptable carrier A pharmaceutical composition for pain suppression in Japan.
(2) The pharmaceutical composition according to the above (1), wherein the cinnamic acid moiety that is cyclized to form a cyclobutane ring has a double bond ratio (crosslinking ratio) of 5% to 40%.
(3) The content of the crosslinked hyaluronic acid is 0.5% (w / v%) to 3.0% (w / v%) of the whole preparation, as described in (1) or (2) above Pharmaceutical composition.
(4) The pharmaceutical composition according to any one of (1) to (3), wherein the pharmaceutical composition is an injection.
(5) The pharmaceutical composition according to (4), wherein the single dose of the injection is 2 to 3 mL.
(6) The pharmaceutical composition according to any one of (1) to (5), which is a single-dose preparation.
(7) The pharmaceutical composition according to (6), wherein the single dose preparation is administered at an administration interval of 13 weeks or more.
(8) The pharmaceutical composition according to any one of (1) to (7), wherein the pharmaceutical composition has a sustained effect for at least 13 weeks.
(9) The pharmaceutical composition according to (8), wherein the pharmaceutical composition has a sustained effect for at least 26 weeks.

(10) The following general formula (1) for use as a pharmaceutical composition for pain suppression in joint diseases;
_{[Ar-CH = CH-COO-} (CH 2) n-NH-] m-HA (1)
(In the formula, Ar represents a phenyl group which may have a substituent, n represents 2 or 3, HA represents a carboxy residue of hyaluronic acid, and m represents amidation with respect to all carboxyl groups of hyaluronic acid. And m is 3 to 50% of the total carboxyl groups.)
Hyaluronic acid crosslinked by cyclizing the double bond of the cinnamic acid moiety of the partially amidated hyaluronic acid represented by formula (II) to form a cyclobutane ring.
(11) The hyaluronic acid according to (10), wherein the cinnamic acid moiety that is cyclized to form a cyclobutane ring has a double bond ratio (crosslinking ratio) of 5% to 40%.
(12) The content of the cross-linked hyaluronic acid in the pharmaceutical composition is 0.5% (w / v%) to 3.0% (w / v%) of the whole pharmaceutical composition (10) Or the hyaluronic acid as described in (11).
(13) The hyaluronic acid according to any one of (10) to (12), wherein the pharmaceutical composition is used as an injection.
(14) The hyaluronic acid according to (13), wherein a single dose of the injection is 2 to 3 mL.
(15) The hyaluronic acid according to any one of (10) to (14), wherein the pharmaceutical composition is a single-dose preparation.
(16) The hyaluronic acid according to (15), wherein the single dose preparation is administered at an administration interval of 13 weeks or more.
(17) The hyaluronic acid according to any one of (10) to (16), wherein the pharmaceutical composition has a sustained effect for at least 13 weeks.
(18) The hyaluronic acid according to the above (17), wherein the pharmaceutical composition has a sustained effect for at least 26 weeks.

(19) To patients who need to suppress pain in joint diseases, the following general formula (1);
_{[Ar-CH = CH-COO-} (CH 2) n-NH-] m-HA (1)
(In the formula, Ar represents a phenyl group which may have a substituent, n represents 2 or 3, HA represents a carboxy residue of hyaluronic acid, and m represents amidation with respect to all carboxyl groups of hyaluronic acid. And m is 3 to 50% of the total carboxyl groups.)
Containing an effective amount of hyaluronic acid crosslinked by cyclizing a cinnamic acid double bond of the partially amidated hyaluronic acid represented by the formula to form a cyclobutane ring, and a pharmaceutically acceptable carrier A method for suppressing pain in a patient who needs to suppress pain in a joint disease, comprising administering a pharmaceutical composition.
(20) The method according to the above (19), wherein the cinnamic acid moiety that is cyclized to form a cyclobutane ring has a double bond ratio (crosslinking ratio) of 5% to 40%.
(21) The content of the crosslinked hyaluronic acid in the pharmaceutical composition is 0.5% (w / v%) to 3.0% (w / v%) of the whole pharmaceutical composition (19) The method described in 1.
(22) The method according to (19) above, wherein the pharmaceutical composition is an injection.
(23) The method according to (22) above, wherein a single dose of the injection is 2 to 3 mL.
(24) The method according to (19) above, wherein the pharmaceutical composition is a single dose preparation.
(25) The method according to (24) above, wherein the single dose preparation is administered at an administration interval of 13 weeks or more.
(26) The method according to (19) above, wherein the pharmaceutical composition has a sustained effect for at least 13 weeks.
(27) The method according to (19) above, wherein the pharmaceutical composition has a sustained effect for at least 26 weeks.

The present invention provides a hyaluronic acid preparation having an early improvement effect on pain caused by joint diseases. In addition, the present invention provides a single-dose preparation with a dose almost the same as conventional ones. The pharmaceutical composition of the present invention shows a rapid pain improving effect after administration, and since this immediate effect is not seen in the conventional IA-HA preparation, a mechanism different from that of the conventional IA-HA preparation is disclosed in the present invention. There is a possibility that the active ingredient is playing. That is, the present invention has been found for the first time that the crosslinked hyaluronic acid used in the present invention has such a possibility.
In addition, the pharmaceutical composition of the present invention is extremely long-lasting for human joint diseases by simply administering a single dose of an IA-HA preparation for multi-dose administration that is almost the same as the single dose. Although the effect of the period is sustained and the injection burden on the patient does not increase so much, a single administration is sufficient, reducing the risk of infection with microorganisms at the time of injection, and multiple puncture pains Will be released. In addition, since the effect lasts for a very long time, it will also contribute to the reduction of the patient's hospital visit and medical expenses. Furthermore, since the administration interval can be made extremely long, continuous treatment with the IA-HA preparation becomes possible.
Furthermore, the pharmaceutical composition of the present invention is particularly preferable as a pharmaceutical composition with few side effects.

It is a figure which shows the pain-inhibition effect in 1 to 13 weeks after administration about a crosslinked hyaluronic acid derivative group and a PBS group. The horizontal axis represents each week after administration, and the vertical axis represents the difference (mm) between the pre-administration reference value (Baseline) and the VAS value in each week. Vertical lines extending above and below the plot at 1, 3, 6, 9, 13 weeks indicate standard deviation. ● shows the results of the cross-linked hyaluronic acid derivative group, and ■ shows the results of the PBS group.

<1> Active ingredient The active ingredient of the present invention is represented by the following general formula (1);
_{[Ar-CH = CH-COO-} (CH 2) n-NH-] m-HA (1)
(In the formula, Ar represents a phenyl group which may have a substituent, n represents 2 or 3, HA represents a carboxy residue of hyaluronic acid, and m represents amidation with respect to all carboxyl groups of hyaluronic acid. And m is 3 to 50% of the total carboxyl groups.)
Is a hyaluronic acid crosslinked by cyclizing the double bond of the cinnamic acid moiety of the partially amidated hyaluronic acid represented by Hereinafter, this compound is referred to as “crosslinked HA derivative”.

  HA constituting this crosslinked HA derivative is composed of a disaccharide unit in which N-acetyl-D-glucosamine and D-glucuronic acid are bonded by a β1,3 bond, and the disaccharide unit is a β1,4 bond. As long as it is a glycosaminoglycan that is constituted by repetitive bonding, it is not particularly limited. Moreover, even if it is a free state which does not form a salt, it may form a pharmaceutically acceptable salt.

As pharmaceutically acceptable salts of HA, alkali metal ion salts such as sodium salt and potassium salt, alkaline earth metal ion salts such as magnesium salt and calcium salt, salts with inorganic bases such as ammonium salt, diethanolamine, Examples thereof include salts with organic bases such as cyclohexylamine and amino acids. As the HA salt, a salt with an alkali metal ion is more preferable, and a salt with a sodium ion is particularly preferable.
HA is produced by culture or genetic engineering techniques using microorganisms such as yeast derived from natural products that are extracted from a part of a living body such as chicken crown, umbilical cord, cartilage and skin. Any of these may be used. In addition, since the crosslinked HA derivative of the present invention is administered to a living body, high-purity HA that does not substantially contain a substance that is not allowed to be mixed as a pharmaceutical is preferable.
Although the weight average molecular weight of HA is not specifically limited, For example, 10,000-5,000,000 is mentioned. Preferably it is 200,000-3,000,000, More preferably, 500,000-2,500,000 is illustrated.

  In the crosslinked HA derivative, a substance (hereinafter also referred to as “photoreactive HA derivative”) in which the carboxyl group in the HA and the cinnamic acid aminoalkyl ester are amide-bonded exists as a premise. And these substances are bridge | crosslinked between molecule | numerators and / or in a molecule | numerator by forming a cyclobutane ring in the double bond part of the said cinnamic-acid aminoalkylester residue.

  In the general formula (1), n represents the length of the alkylene moiety in the cinnamic acid aminoalkyl ester, and n is 2 or 3, that is, preferably having 2 or 3 carbon atoms, and particularly preferably having a straight chain. Preferably, an ethylene group or a trimethylene group is mentioned, for example. Examples of cinnamic acid ester in the present invention include cinnamic acid 2-aminoethyl ester or cinnamic acid 3-aminopropyl ester, and preferable cinnamic acid ester includes cinnamic acid 3-aminopropyl ester. In the following description, cinnamic acid 3-aminopropyl ester is simply referred to as cinnamic acid aminopropyl ester, and is based on this. It will be readily understood that cinnamic acid aminoethyl ester can be substituted for cinnamic acid aminopropyl ester described below as well.

The photoreactive HA derivative can be produced by amide-bonding an amino group derived from aminopropanol constituting cinnamic acid aminopropyl ester with a carboxyl group of HA.
Such cinnamic acid aminopropyl ester is an ester compound in which the carboxyl group of cinnamic acid and the hydroxyl group of 3-aminopropanol are bonded by an ester bond. This cinnamic acid aminopropyl ester can form a cyclobutane ring with vinylene groups of cinnamic acid. The vinylene group possessed by cinnamic acid has a property of causing a photodimerization reaction or a photopolymerization reaction when irradiated with light (ultraviolet rays). Therefore, a cyclobutane ring is formed by two vinylene groups by light irradiation. The cinnamic acid constituting the cinnamic acid 3-aminopropyl ester may be a substituted cinnamic acid having a substituent.

Ar in the said General formula (1) shows the phenyl which may have a substituent. In the general formula (1), when Ar is a phenyl group having no substituent, it becomes a cinnamic acid ester, and when Ar has a substituent, it becomes a substituted cinnamic acid ester. Examples of such substituents include any one or two hydrogens on the benzene ring of cinnamic acid are linear or branched lower alkyl groups having 1 to 8 carbon atoms (eg, methyl, ethyl , Propyl, isopropyl, butyl, t-butyl, etc.), a linear or branched lower alkoxy group having 1 to 8 carbon atoms (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), the alkyl group Examples thereof include an optionally substituted amino group, hydroxyl group and halogen.
In the photoreactive HA derivative, not all of the carboxyl groups in HA need to be amide-bonded to cinnamic acid aminopropyl ester, and a part of them may be amide-bonded.

In the general formula (1), m represents the ratio (%) of amide bond with cinnamic acid aminoalkyl ester to the total carboxyl groups of HA. Hereinafter, the ratio (m) in which amide bonds are formed out of all carboxyl groups present in HA is referred to as “introduction rate” (DS). DS was calculated by the percentage introduction of cinnamic acid aminopropyl ester residues per constituent disaccharide unit of HA, for example, one cinnamic acid aminopropyl ester residue was introduced per constituent disaccharide unit. The DS of the photoreactive HA derivative or the photoreactive HA derivative in which one cinnamate aminopropyl ester residue is introduced per 200 saccharide units is 100% and 1%, respectively.
DS in the photoreactive HA derivative in the present invention, that is, m is not particularly limited, but is preferably 3% to 50%, more preferably 5% to 30%, and even more preferably 10% to 25%.

The crosslinked HA derivative used in the present invention can be produced according to the methods described in JP 2002-249501 A, WO 2008/069348 pamphlet and the like.
For example, it is not particularly limited as long as it is a method capable of chemically binding cinnamic acid aminopropyl ester and HA by an amide bond. For example, water-soluble carbodiimide (eg, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI · HCl), 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide-meth-p-toluenesulfone A method using a water-soluble condensing agent such as an acid salt, a method using a condensing aid such as N-hydroxysuccinimide (HOSu) and N-hydroxybenzotriazole (HOBt) and the above condensing agent, 4- (4 , 6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM), a method using a condensing agent, an active ester method, an acid anhydride method, and the like. .

  The photoreactive HA derivative is prepared by previously reacting cinnamic acid with aminopropanol (for example, 3-aminopropanol, the same shall apply hereinafter) to cinnamic acid aminopropyl ester (for example, cinnamic acid 3-aminopropyl ester, hereinafter the same shall apply). And amide bond between the amino group of the prepared cinnamic acid aminopropyl ester and the carboxyl group of HA, or the amide bond between the amino group of aminopropanol and the carboxyl group of HA. HA having aminopropanol introduced thereinto may be prepared, and then the carboxyl group of cinnamic acid may be ester-bonded with the aminopropanol-derived hydroxyl group in HA into which the prepared aminopropanol has been introduced.

The crosslinked HA derivative is a compound in which the photoreactive HA derivatives as described above are bonded together by forming a cyclobutane ring at the double bond portion of the cinnamate propyl ester residue present in the derivative. is there.
A method for forming a cyclobutane ring in the double bond portion of the cinnamate propyl ester residue is not particularly limited. For example, the cinnamate propyl ester residues are photodimerized or photopolymerized in a solution of a photoreactive HA derivative. A method of performing light irradiation under conditions that cause a chemical reaction can be exemplified. The light irradiation in this case is not particularly limited as long as it is light that does not cleave the glycosidic bond of HA and causes a photoreaction to occur on the cinnamate propyl ester residue. Illustrative is ultraviolet light of ˜400 nm. The intensity of irradiation light can be appropriately selected according to the properties required for the crosslinked HA derivative. As a preferable light irradiation device, an ultraviolet lamp, a high-pressure mercury lamp, a metal halide lamp, or the like can be used. If necessary, it is preferable to remove light having an unnecessary wavelength from the light source, for example, with a cut filter or the like.

In the crosslinked HA derivative, it is not necessary that all the double bond portions of the cinnamate propyl ester residue in the photoreactive HA derivative are bonded by forming a cyclobutane ring, and only a part of the double bond portion has a cyclobutane ring. It may be formed and bonded.
Hereinafter, the ratio (%) of cinnamate propyl ester residues contributing to the formation of the cyclobutane ring structure out of the cinnamate propyl ester residues present in the photoreactive HA derivative in the crosslinked HA derivative is expressed as “crosslinking. "Rate". For example, in a photoreactive HA derivative having 100 cinnamate propyl ester residues introduced, if 20 cinnamate propyl ester residues (monomers) are dimerized, 10 dimers are produced, The crosslinking rate is 20%.

Although the crosslinking rate in the crosslinked HA derivative used in the present invention is not particularly limited, 5% to 40% is preferable, 7% to 35% is more preferable, and 10% to 30% is still more preferable.
When the formation of the cyclobutane ring is performed by crosslinking using the light irradiation, a preferable reaction solution concentration when performing the crosslinking is preferably 0.5% to 3.0%, more preferably 0.7% to 2%.

  The crosslinked HA derivative may be in a free state that does not form a salt, or may form a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable salt of the crosslinked HA derivative include sodium salt, potassium salt, magnesium salt, calcium salt and the like.

<2> Content of the crosslinked HA derivative of the present invention The crosslinked HA derivative has a three-dimensional network structure. Therefore, a solution in which a crosslinked HA derivative is dissolved in an aqueous medium has the physical properties of a hydrogel having viscoelasticity, and particularly exhibits higher viscoelasticity than an aqueous HA sodium solution prepared at the same concentration.
The content of the crosslinked HA derivative in the medicinal light composition of the present invention is preferably 0.5% (w / v%) to 3.0% (w / v%). More preferably, it is 0.7% (w / v%) to 2.0% (w / v%), more preferably 1.0% (w / v%).

The pharmaceutical composition of the present invention can be in various dosage forms, but it is usually preferable to use an injection as a liquid for injection.
By setting the content as described above, moderate fluidity can be imparted for intra-articular administration using a syringe equipped with an injection needle, and it passes through an 18 gauge to 25 gauge injection needle, It can be used as an injection for intra-articular administration (composition for injection).

<3> Dosage of Pharmaceutical Composition of the Present Invention, etc. The pharmaceutical composition of the present invention is administered into human joints, particularly into knee joints. For example, in the case of single administration into the knee joint, 2 to 5 mL, preferably 2 to 3 mL is preferably administered. The dosage of the pharmaceutical composition of the present invention can be administered in the same or almost the same dosage as that of a conventional multiple-dose IA-HA preparation.
Further, in one intra-knee joint administration, the weight of the photoreactive HA derivative will be a normal dose range of 15 mg to 60 mg per adult patient (50 to 70 kg), preferably 25 mg to 35 mg, particularly preferably 30 mg. Furthermore, the dosage (solution volume) may be further reduced.
The pharmaceutical composition of the present invention can be administered at a dosing interval of one week or more as in the conventional IA-HA preparation. In the pharmaceutical composition of the present invention, the pain-reducing action appears early, and the effect lasts for a long period of time. Therefore, the administration interval can be made longer than that of conventional IA-HA preparations. Since the action of the pharmaceutical composition of the present invention lasts for 13 weeks or more, more specifically 13 to 26 weeks, the administration interval may be 13 weeks or more, and further 13 to 26 weeks. it can. The pharmaceutical composition of the present invention can be used to maintain an effect for at least 13 weeks, and further to maintain an effect for 26 weeks. Given that the current series of treatments for IA-HA preparations is every 26 weeks, the pharmaceutical composition of the present invention can be administered continuously every 26 weeks and can be administered continuously in a single dose. -It can also be called HA formulation.

<4> Applicable subjects of the pharmaceutical composition of the present invention The pharmaceutical composition of the present invention has a pain suppressing effect or a pain improving effect on human joint diseases. The pharmaceutical composition of the present invention exhibits a therapeutic effect at an early stage after administration, and starts to show a maximum effect after 1 to 3 weeks after administration, and the effect lasts for 13 weeks or more, and further for 26 weeks. To do. This “therapeutic effect” is not particularly limited as long as it is an effect of improving the symptoms of human joint disease, and examples thereof include an improvement effect of physical function, an improvement effect of stiffness, an effect of suppressing pain, etc. It is preferable that it is an effect.
The pharmaceutical composition of the present invention is characterized in that after a single administration, such an improving effect is manifested after 1 to 3 weeks and lasts for a very long period of at least 13 weeks or even 26 weeks.

  In the pharmaceutical composition of the present invention, as long as the desired effect is not lost and side effects do not occur, the solvent, pH adjuster, and isotonicity used in the preparation of a normal injectable preparation as necessary. It may contain additives such as agents and stabilizers. For example, as a solvent for the crosslinked HA derivative, water for injection, physiological saline, phosphate buffered saline and the like are exemplified, and phosphorus used as a pH adjusting agent and an isotonic agent in the preparation of a usual injection preparation. Examples of the additive include sodium dihydrogen acid, sodium hydrogen phosphate, sodium chloride and the like.

In addition, the pharmaceutical composition of the present invention provides a remarkable therapeutic effect early after a single administration. As shown in the Examples described later, particularly, the pain suppressing effect is more than about 90% of the maximum therapeutic effect at 3 weeks after the administration of the pharmaceutical composition of the present invention. Such a rapid action and conspicuousness in the pharmaceutical composition of the present invention is not found in the conventional IA-HA preparation, and therefore a mechanism different from that of the conventional IA-HA preparation, for example, rapid action analgesia. It is also conceivable that the active ingredient of the present invention has an action like action. That is, the present invention has found for the first time the possibility that the crosslinked HA derivative of the present invention has a pain improving action by a mechanism different from the hyaluronic acid component in the conventional IA-HA preparation.
In addition, as shown in the examples described later, even in the 26th week after the first single administration, a patient who developed pain again before re-treatment was required was compared with a PBS administration patient. The number of groups administered was significantly less, and this result shows that the recurrence of pain is significantly delayed by the administration of the pharmaceutical composition of the present invention.

  For reference, ARTZ (registered trademark, manufactured by Seikagaku Corporation), which is one of the commercially available IA-HA preparations, is an intra-articular injection solution of 1 ampule or 1 syringe 2.5 mL. Administer 1 ampoule or 1 syringe at a time 5 times per week. Therefore, the amount used for a single treatment of ARTZ is 12.5 mL. Synvisc-One (trademark; manufactured by Genzyme) is used as a prescription in a single injection of 6 mL in one injection.

  Accordingly, the pharmaceutical composition of the present invention is administered, for example, once every 3 months to 6 months for chronic joint diseases based on the three main merits of single administration, small dosage, and long therapeutic effect. It can also be used as a dosage formulation for the purpose. Of course, it can be used as a preparation for administration at intervals of 6 months or more in consideration of the duration of improvement effect and symptoms in patients. Needless to say, only one administration, ie, only one treatment is possible.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, this does not limit the technical scope of this invention.

[Synthesis Example] Preparation of Cross-linked HA Derivative Using sodium hyaluronate having a weight average molecular weight of 90 to 1,000,000 and 3-aminopropyl hydrochloride of cinnamic acid as raw materials, the introduction rate is 10 to 25% according to the description of WO2008 / 069348 and A cross-linked hyaluronic acid derivative solution having a concentration of 1.0 (w / v)% was prepared as appropriate so that the cross-linking rate was 10 to 30%. This solution is hereinafter referred to as “test substance”.

[Test procedure]
For patients with knee osteoarthritis, a multicenter double-blind parallel group comparison study was conducted to verify the effectiveness of a single administration of the crosslinked HA derivative of the present invention. As a placebo (control), phosphate buffered saline (PBS) was used.
One to two weeks before administration of the test substance, patients were screened based on the following selection criteria and exclusion criteria. Patients who met the criteria were randomly divided into a cross-linked HA derivative administration group and a PBS administration group of the present invention. There were 249 crosslinked HA derivative groups and 128 PBS groups (total of 377).

To the patients in the cross-linked HA derivative administration group of the present invention, the above-mentioned test substance was injected once into the joint of one affected knee at a dose of 3 mL / joint. PBS patients received a single injection of PBS in the same manner. In addition, the doctor who performed administration confirmed the affected knee of the patient to administer before administration, and when the edema existed, the joint reservoir was aspirated.
After the injection, the improvement effect was evaluated based on the evaluation method described later at each of the first, third, sixth, ninth, and thirteenth weeks.
On each evaluation day, acetaminophen was distributed as a concomitant drug and allowed to be taken up to 4,000 mg per day. In addition to acetaminophen, non-steroidal anti-inflammatory analgesics, over-the-counter drugs (OTC), herbal remedies, cartilage protectants only when taking a fixed dose for 4 weeks before administration of the test substance. Was allowed to take. In addition, intermittent use of opioid analgesics during the test period was allowed. However, any combination therapy was prohibited for 24 hours before each evaluation day.

[Selection criteria, exclusion criteria]
(1) Selection criteria Patients who satisfy all of the following conditions can be eligible for this study, except for those who fall under any of the exclusion criteria described below.
・ Patients with knee osteoarthritis symptoms between 40 and 80 years old.
-Patients with knee pain when standing or walking for at least 4 weeks.
・ Patients judged as Kellgren-Larence classification grade 1 to 3 by X-ray findings.
・ Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC (registered trademark)) Patients whose target knee is 40 mm or more and the opposite knee is 20 mm or less. As WOMAC (registered trademark), Visual analog scale (VAS) 100 mm was used.
・ Patients who have agreed to discontinue the current treatment, excluding acceptable combination therapy, during the study period.
(2) Those who are judged as Kellgren-Larence classification grade 4 by exclusion criteria and X-ray findings.
・ Patients with inflammatory diseases other than OA in the target knee, those with severe knee joint edema, or those with severe changes in lower limb alignment.
-Those who have undergone knee or hip joint surgery, those who have performed knee joint surgery within 12 months, those who have performed arthroscopy within 3 months, those who have received intra-articular hyaluronic acid preparation within 6 weeks .
・ Those who have serious systemic disease or infectious skin disease on the knee to be evaluated.

[Evaluation method]
The effectiveness of cross-linked HA derivatives was evaluated using the WOMAC evaluation developed by Dr. Nicholas Bellamy (The Journal of Rheumatology 1988; 15:12, p.1833-1840). WOMAC is a registered trademark. Hereinafter, the indication of the registered trademark is omitted.
The WOMAC evaluation used here is based on the answers of 24 questions (Total) consisting of three parts, Pain, Stiffness, and Physical function, to the patient. It is a method to evaluate.
In this study, WOMAC pain evaluation (Pain) was used as the main evaluation, and WOMAC stiffness evaluation (Stiffness), WOMAC physical function evaluation (physical function), and WOMAC all item evaluation (Total) were used as secondary evaluations. Using.
WOMAC evaluation has been established as an OA evaluation method, and as described above, is a patient-reported evaluation method consisting of a total of 24 questions including pain, physical function, and stiffness. There are two types of question answering methods: VAS (Visual Analog Scale) and Likert scale. VAS is a method in which a patient indicates the degree of touch of each patient with respect to each question on a straight line of 100 mm, and the degree is determined based on the position. The position is expressed as a length from the left end on the scale. On the other hand, the Likert Scale is a method in which the patient indicates the degree of the patient's own feeling with respect to each question by using five choices of answer options. In this study, VAS evaluated the patient's pain, physical function, and stiffness.

For example, the patient is asked the same questions regarding pain at each evaluation before and after administration, and the patient answers by indicating the position (degree) on the scale. Based on the difference between the length indicated by the patient before administration (baseline before administration) and the length indicated by the patient at each evaluation after administration, the improvement effect is quantified.
WOMAC evaluation is widely used as an index of OA treatment effect, and the credibility and reliability of using WOMAC evaluation for OA treatment effect is recognized (The Journal of Rheumatology 2000; 27:11, p.2635-2641). ).

Intention-to-treat population (ITT population) and per protocol population (PP population) were used for the analysis of effectiveness. The ITT population was a total of 375 people consisting of 247 cross-linked HA derivative groups of the present invention and 128 PBS groups. Two patients who did not go to hospital after administration were deleted.
The PP population was a total of 344 people consisting of 229 people of the crosslinked HA derivative group of the present invention and 115 people of the PBS group. Patients who deviated from the conditions of this study were deleted.

[result]
The results of PP population analysis for WOMAC pain evaluation are shown in Table 1, and the results of ITT population analysis are shown in Table 2.

The cross-linked HA derivative of the present invention was confirmed to have a statistically significant improvement with respect to PBS at 3 weeks after administration, and a remarkable effect was confirmed after 3 weeks. In the PP population, the p-values at 3 weeks, 6 weeks and 13 weeks were 0.05 or less, and there was a statistically significant difference from PBS. The cross-linked HA derivative of the present invention was not significantly different at 9 weeks, but an improvement trend was confirmed.
Moreover, the model graph which showed the regression analysis result using ITT population is shown in FIG. Analysis of the improvement in pain 13 weeks after administration revealed that the crosslinked HA derivative-administered group statistically significantly improved pain compared to the PBS-administered group from 1 to 13 weeks and from 3 to 13 weeks. From week 1 to week 13 after administration, p-value = 0.0483, and from week 3 to week 13 after administration, p-value = 0.0495, both of which show statistically significant differences with respect to PBS. It was.

Furthermore, the improvement of each WOMAC evaluation at the 13th week was analyzed using PP population by the regression model. The results are shown in Table 3. At 13 weeks after administration, it was confirmed that the crosslinked HA derivative improved the pain statistically significantly compared to PBS. Regarding the secondary efficacy evaluation items, WOMAC all item evaluation and WOMAC body function evaluation, statistically significant improvement of the crosslinked HA derivative was confirmed, and there was a statistically significant difference from PBS. The WOMAC stiffness evaluation did not produce a statistically significant difference, but a significant trend in the crosslinked HA derivative was confirmed.
The calculated difference is a difference calculated using a regression model and is translated as Estimated difference.

In addition, when Strict OMERACT-OARSI Response was analyzed to verify clinical usefulness, a statistically significant improvement of the crosslinked HA derivative was observed (see Table 4).
In Strict OMERACT-OARSI Response, patients who have improved by more than 50% and 20 mm or more from the pre-dose baseline (Baseline) in WOMAC pain evaluation or WOMAC physical function evaluation are markedly improved. The total of these improvement groups is called Strict OMERACT-OARSI responder.

  In addition, with regard to the expression of early improvement effects, with respect to WOMAC pain evaluation, WOMAC all item evaluation, WOMAC physical function evaluation, and WOMAC stiffness evaluation, the average improvement from baseline in the third week was determined for the crosslinked HA derivative group and the PBS group. Compared and verified. The WOMAC pain evaluation obtained an improvement effect exceeding 90% of the maximum improvement effect in the third week, and a p-value representing the statistical significance of the crosslinked HA derivative against PBS was calculated (Table 5). In any evaluation item, the p value was smaller than 0.05 (p <0.05), and a statistically significant difference was shown.

Furthermore, after observing 13 weeks after administration of the crosslinked HA derivative or PBS, continuous observation was continued for another 13 weeks, and the effectiveness of the crosslinked HA derivative group up to 26 weeks after the initial administration was verified.
WOMAC pain assessment was performed 16, 19, 22, and 26 weeks after the first administration, and survival analysis of each treatment group was performed using the Cox-hazard model, with patients not satisfying the following criteria as the sustained efficacy group of the first administration. .
Criteria A: Having pain of VAS 40 mm or more in WOMAC pain evaluation.
Criteria B: VAS 40 mm or more in WOMAC pain evaluation,
And it has an improvement of less than 20 mm from the reference value before the first administration.
When Cox-hazard analysis was used, in both criteria, the cross-linked HA derivative administration group showed efficacy up to 26 weeks (Criteria A: p = 0.199, Criteria B: p = 0.027).

[Conclusion]
It was confirmed that a single injection of the crosslinked HA derivative showed an improving effect that lasted for at least 26 weeks after the injection.
The cross-linked HA derivative showed a marked improvement over PBS not only in the evaluation of pain but also in the evaluation of physical function, and multifaceted effectiveness was confirmed in joint diseases.
Moreover, the early onset of the pain improving effect could be confirmed 3 weeks after the injection, and a statistically significant difference was also shown in comparison with PBS.
Furthermore, the crosslinked HA derivative showed a significant improvement effect up to 13 weeks and even up to 26 weeks. In addition, the incidence of adverse events in the cross-linked HA derivative group is not statistically significantly different from that in the PBS group, and there are no serious side effects, and the safety of the cross-linked HA derivative as an intra-articular injection is high. confirmed.

  The present invention provides a novel joint disease pain suppressing agent that exhibits a pain suppressing effect at an early stage after administration and has a long-term persistence of 13 to 26 weeks, and the burden on patients is greatly improved. Therefore, it has industrial applicability in the pharmaceutical industry and the like.

Claims (2)

The following general formula (1);
_{[Ar-CH = CH-COO-} (CH 2) n-NH-] m-HA (1)
(In the formula, Ar represents a phenyl group which may have a substituent, n represents 2 or 3, HA represents a carboxy residue of hyaluronic acid, and m represents amidation with respect to all carboxyl groups of hyaluronic acid. And m is 3 to 50% of the total carboxyl groups.)
In a double bond of cinnamic acid moiety represented by partial amidation hyaluronic acid, hyaluronic acid crosslinked by is cyclized to form a cyclobutane ring, and comprising a pharmaceutically acceptable carrier, single A human joint disease therapeutic agent which is a single dose preparation , wherein the joint disease therapeutic agent is an injection, and a single dose of the injection is 2 to 3 mL and the weight of the crosslinked hyaluronic acid is 30 mg. A therapeutic agent for joint diseases . The joint disease therapeutic agent according to claim 1, wherein the content of the crosslinked hyaluronic acid is 1% (w / v%) of the whole preparation, and the single dose of the injection is 3 mL.